Specific aims of this multidisciplinary program proposal include: 1) an investigation of the hypothesis that Alzheimer's Disease (AD) is one of several systemic, genetically determined illnesses which result from primary dysfunction of certain enzymes derived from the mitochondrial genome; 2) an evaluation of blood platelet cytochrome oxidase (cytox, complex IV) levels in patients with probable AD, Parkinson's Disease (PD) and normal controls to determine the diagnostic utility of this assay; 3) a comparison of levels of platelet complex I activity in patients with PD, their close relatives, normal controls and patients with "PD-plus" syndromes; 4) validation of the hypothesis that some elderly patients with dementia and other neuropsychiatric abnormalities have significant cobalamin (vitamin B12) deficiency which is responsive to cobalamin therapy; 5) an analysis of the distribution and quantity of sodium channels in experimentally demyelinated axons, and in aged and young animal and human nervous tissues. Long term objectives are: 1) better understanding of a basic biochemical defect in AD and of the general concept of mitochondrial inheritance which might lead to therapy; 2) development of specific diagnostic blood tests for AD and PD; 3) clarification of the inheritance pattern of AD and PD; 4) potential treatment for asymptomatic carriers of AD and PD if agents, such as selegiline and/or antioxidants in PD, can be shown to prevent or delay manifest disease; 5) expansion of the list of treatable dementias by utilizing blood and CSF analysis of cobalamin metabolites; 6) understanding changes in axonal and neuronal sodium channels in normal aging and dementia. In Project 1, cytochrome oxidase from AD brain will be studied biochemically. Mitochondrial DNA from AD patients will be sequenced. Projects 2 & 3 will examine platelet levels of Complex IV & I, respectively, in AD & PD. Project 4 will correlate blood and CSF levels of cobalamin and/or metabolites with various neuropsychiatric abnormalities, such as dementia, in appropriate patients and determine response to therapy. Project 5 will utilize sodium channel-specific antibodies in demyelinated axons and peripheral and central nervous tissue of fish, rats and humans to determine abnormalities that result in neuronal and axonal dysfunction. Core A provides clinical, neuropathological and statistical support while Core B provides administrative assistance.